3-(Amino- or aminoalkyl)pyridinone derivatives and their use for the treatment of HIV related diseases

• US 6,451,822 B1
• Filed: 01/05/2001
• Issued: 09/17/2002
• Est. Priority Date: 04/27/1998
• Status: Expired due to Fees

• Current Assignee: Centre National De La Recherche Scientifique, Institut Curie
• Original Assignee: Centre National De La Recherche Scientifique, Institut Curie
• Inventors: Nguyen, Chi Hung, Dolle, Valérie, Grierson, David, Bisagni, Emile, Monneret, Claude, Aubertin, Anne-Marie
• Primary Examiner(s): Rotman, Alan L.
• Assistant Examiner(s): DESAI, RITA J
• Application Number:
  US09/673,635
• Time in Patent Office: 620 Days
• Field of Search: 546/297, 546/298, 546/300, 514/349, 514/350, 514/351
• US Class Current: 514/349
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07D 213/73 Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention is concerned with 3-(amino- or aminoalkyl)pyridinone derivatives which inhibit the reverse transcriptase of the Human Immunodeficiency Virus (HIV). It relates moreover to the use of such compounds for treating HIV-related diseases. Furthermore it relates to a process for the preparation of these compounds.

Claims

1. A compound having the formula (1)

wherein:

Q represents —

NR₁R₂ or —

R₀NR₁R₂ wherein;

R₀ represents C_1-6 alkanediyl;

R₁ and R₂ each independently represent C_1-6 alkyl or C_3-6 alkenyl;

said C_1-6 alkyl and C_3-6 alkenyl may be substituted with one, two or three substituents selected from the group consisting of hydroxy, C_1-4 alkyloxy, C_1-4 alkylthio, aryloxy, arylthio, amino, mono- and di(C_1-4alkyl)amino, and aryl;

R₃ represents aryl;

R₄ and R₅ each independently represent hydrogen, C_1-6 alkyl, C_3-6 alkenyl, C_1-4 alkoxy, C_1-4 alkoxyC_1-4 alkyl, amino, mono- or di(C_1-4alkyl)amino, formyl, C_1-4 alkylcarbonyl carboxyl, C_1-4 alkyloxycarbonyl, or C_1-4 alkyl aminocarbonyl;

wherein C_1-6 alkyl and C_3-6 alkenyl may be substituted with one, two or three substituents selected from the group consisting of hydroxy, C_1-4 alkyloxy, C_1-4 alkylthio, aryloxy, arylthio, amino, mono- or di(C_1-4alkyl)amino and aryl;

R₆ represents hydrogen, hydroxy, C_1-4 alkyloxy, C_1-6 alkyl, C_3-6 alkenyl, aryl, C_1-4 alkyl, amino, mono- or di(C_1-4alkyl)amino or alkylaryl;

Y represents O or S;

X represents a radical of formula;

 

—

(CH₂)_p 

 

(a)

or

2. The compound according to claim 1, wherein R₁ and R₂ each represent a methyl group.

3. The compound according to claim 1, wherein X represents —

CH₂— and

R₃ represents a phenyl group substituted with two methyl groups.

4. The compound according to claim 1 which is 3-dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one.

5. A process for obtaining a compound according to claim 1, wherein X represents —

CH₂—

, Y represents O, R₃ is an optionally-substituted phenyl group, and R₆ is hydrogen, said process comprising the following steps;

a) reacting a pyridine, substituted in position 2 with an alkoxy group and in position 3 with an amidoalkyl group, with a C₁-C₆ alkyllithium, to obtain a lithiated derivative of said pyridine;

b) reacting said lithiated derivative with a complex formed by CuI and dimethyl sulfide, to obtain an organocopper reagent;

c) reacting said organocopper reagent with an optionally substituted benzyl halide, to obtaining a protected pyridinone;

d) hydrolyzing said protected pyridinone, to obtain a deprotected pyridinone; and

e) substituting the amine-3 group of said deprotected pyridinone, to obtain said pyridinone compound.

6. A process for obtaining a compound according to claim 1, wherein X represents —

C(═

O), Y represents O, R₃ is an optionally substituted phenyl group, and R₆ is hydrogen, wherein said process comprises;

a) reacting a pyridine, substituted in position 2 with an alkoxy group and in position 3 with an amidoalkyl group, with a C₁-C₆ alkyllithium, to obtain a lithiated derivative of said pyridine;

b) reacting said lithiated derivative with an optionally substituted benzaldehyde, to obtain a substituted pyridinone;

c) oxidizing said substituted pyridinone, to obtain a protected pyridinone; and

d) deprotecting said protected pyridinone by hydrolysis, to obtain said pyridinone compound.

7. A pharmaceutical composition, comprising a therapeutically effective amount of at least one compound according to claim 1 and a pharmaceutical carrier.

8. The pharmaceutical composition of claim 7, wherein in said compound according to claim 1, R₁ and R₂ each represent a methyl group.

9. The pharmaceutical composition of claim 7, wherein in said compound according to claim 1, X represents —

CH₂— and

R₃ represents a phenyl group substituted with two methyl groups.

10. The pharmaceutical composition of claim 7, wherein said compound according to claim 1 is 3-dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one.

11. A method for treating HIV-related disease wherein said method comprises a step of administering to a patient an effective amount of a compound according to claim 1.

12. The method of claim 11, wherein in said compound according to claim 1, R₁ and R₂ each represent a methyl group.

13. The method of claim 11, wherein in said compound according to claim 1, X represents —

CH₂— and

R₃ represents a phenyl group substituted with two methyl groups.

14. The method of claim 11, wherein said compound according to claim 1 is 3-dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one.

15. A method for treating an HIV-infection, wherein said method comprises a step of administering to a patient an effective amount of a compound according to claim 1.

16. The method of claim 15, wherein in said compound according to claim 1, R₁ and R₂ each represent a methyl group.

17. The method of claim 15, wherein in said compound according to claim 1, X represents —

CH₂— and

R₃ represents a phenyl group substituted with two methyl groups.

18. The method of claim 15, wherein said compound according to claim 1 is 3-dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one.